Dezofemono® 75

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DEZOFEMONE® 75

Composition:

Active substance: desogestrel;

1 tablet contains 0.075 mg of desogestrel;

Excipients: lactose monohydrate, corn starch, maltodextrin, SepiFilm transparent isolating coating mixture (hypromellose 6 cP, hypromellose 15 cP, microcrystalline cellulose, stearic acid), sodium starch glycolate (type A), α-tocopherol, white film-coating mixture (hypromellose, lactose monohydrate, titanium dioxide (E171), macrogol 4000, sodium citrate).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, biconvex tablets with a triangular imprint on one side, coated with a white film.

Pharmacotherapeutic group. Systemic hormonal contraceptives. ATC code: G03AC09.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Desofemone® 75 is a progestogen-only contraceptive containing the progestogen desogestrel. Like other progestogen-only contraceptives, Desofemone® 75 can be used by women who cannot or do not wish to take estrogens. Unlike traditional progestogen-only contraceptives, the contraceptive effect of Desofemone® 75 is achieved primarily through suppression of ovulation. Other effects include increased viscosity of cervical mucus.

Clinical Efficacy and Safety

In a study conducted over two cycles, in which ovulation was defined by serum progesterone levels exceeding 16 nmol/L for five consecutive days, ovulation occurred in 1% (1/103) of cases with a 95% confidence interval (CI) of 0.02–5.29% in the group initiating treatment (users and method failure). Ovulation suppression was achieved starting from the first cycle. In this study, when administration of the desogestrel-only drug was discontinued after two cycles (56 consecutive days of drug intake), ovulation occurred on average 17 days later (range 7–30 days).

In a comparative efficacy study (in which missed tablets were allowed to be taken up to 3 hours after the scheduled time), the overall Pearl Index in the group initiating treatment with a drug containing 0.075 mg desogestrel was 0.4 (95% CI 0.09–1.20), compared to 1.6 (95% CI 0.42–3.96) for 30 mcg levonorgestrel.

The Pearl Index for Desofemone® 75 is comparable to that established for combined oral contraceptives (COCs) in the general population using COCs.

Use of Desofemone® 75 results in a reduction of serum estradiol levels to those typical of the early follicular phase. No clinically significant effects on carbohydrate metabolism, lipid metabolism, or hemostasis were observed.

Children

There are no clinical data on the efficacy and safety of the drug in adolescents under 18 years of age.

Pharmacokinetics

Absorption

After oral administration of desogestrel (DSG), the drug is rapidly absorbed and converted into its biologically active metabolite, etonogestrel (ENG). At steady state, peak serum concentrations are reached approximately 1.8 hours after tablet intake, and the absolute bioavailability of ENG is approximately 70%.

Distribution

ENG is 95.5–99% bound to serum proteins (primarily albumin), and to a lesser extent to sex hormone-binding globulin.

Biotransformation

DSG is metabolized via hydroxylation and dehydrogenation to form the active metabolite ENG. ENG is metabolized primarily by the cytochrome P450 3A (CYP3A) isoenzyme, followed by conjugation with sulfate and glucuronide.

Elimination

The elimination half-life of ENG is approximately 30 hours, both after single and multiple doses. Steady-state plasma levels are reached within 4–5 days. The serum clearance after intravenous administration of ENG is approximately 10 L/h. Elimination of ENG and its metabolites, both as free steroid and as conjugates, occurs via urine and feces (in a ratio of 1.5:1). In breastfeeding women, ENG is excreted into breast milk at a milk-to-plasma ratio of 0.37–0.55. Based on these data and an estimated milk intake of 150 mL/kg/day by the infant, the infant may receive 0.01–0.05 mcg of etonogestrel.

Special Patient Groups

Patients with Renal Impairment

Studies on the effect of renal disease on the pharmacokinetics of DSG have not been conducted.

Patients with Hepatic Impairment

Studies on the effect of liver disease on the pharmacokinetics of DSG have not been conducted. However, in women with impaired liver function, metabolism of sex hormones may be reduced.

Ethnic Groups

Pharmacokinetic studies in ethnic groups have not been conducted.

Clinical characteristics.

Indications.

Contraception.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients listed in the section "Composition".

Established or suspected pregnancy.

Venous thromboembolic disorders in the active phase.

History of or existing severe liver disease — until liver function has normalized.

Diagnosed or suspected hormonally dependent malignant tumors.

Vaginal bleeding of unknown etiology.

Interaction with other medicinal products and other forms of interaction.

Note. It is necessary to carefully read the instructions for medical use of the concomitant medicinal product to identify possible interactions.

Effect of other medicinal products on Desofemono® 75

Interaction may occur with medicinal products that induce microsomal enzymes, leading to increased clearance of sex hormones and breakthrough bleeding and/or contraceptive failure.

Actions to take

Enzyme induction may be observed after several days of treatment. Maximum enzyme induction is usually observed after several weeks. After discontinuation of the medicinal product, enzyme induction may persist for up to 4 weeks.

Short-term treatment

Women taking medicinal products or herbal preparations that induce hepatic enzyme activity should be warned about the reduced efficacy of Desofemono® 75. In addition to Desofemono® 75, a barrier method of contraception should be used. The barrier method should be used throughout the duration of concomitant therapy and for 28 days after discontinuation of the medicinal product causing hepatic enzyme induction.

Long-term treatment

For women receiving long-term therapy with medicinal products that induce enzyme activity, an alternative method of contraception should be selected that is not affected by enzyme-inducing medicinal products.

Substances that increase the clearance of contraceptive hormones (reduced contraceptive efficacy due to enzyme induction), e.g.: barbiturates, bosentan, carbamazepine, phenytoin, primidone, rifampicin, efavirenz, and possibly felbamate, griseofulvin, oxcarbazepine, topiramate, rifabutin, and herbal preparations containing St John's wort (Hypericum perforatum).

Substances with variable effects on contraceptive hormone clearance

When used concomitantly with hormonal contraceptives, a large number of combinations of HIV protease inhibitors (e.g., ritonavir, nelfinavir) and non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine), including combinations with hepatitis C virus (HCV) protease inhibitors (e.g., boceprevir, telaprevir), may increase or decrease plasma concentrations of progestins. In some cases, the overall effect of these changes may be clinically significant.

Therefore, to identify possible interactions and provide appropriate recommendations, the instructions for medical use of concomitant medicinal products for the treatment of HIV/hepatitis C virus should be consulted. In case of any doubt, women should additionally use a barrier method of contraception during therapy with a protease inhibitor or non-nucleoside reverse transcriptase inhibitor.

Substances that reduce contraceptive hormone clearance (enzyme inhibitors)

Concomitant use with strong (e.g., ketoconazole, itraconazole, clarithromycin) or moderate (e.g., fluconazole, diltiazem, erythromycin) CYP3A4 inhibitors may lead to increased serum concentrations of progestins, including etonogestrel, the active metabolite of desogestrel.

Effect of Desofemono® 75 on other medicinal products.

Hormonal contraceptives may affect the metabolism of other medicinal products. Accordingly, plasma and tissue concentrations of other active substances may either increase (e.g., cyclosporine) or decrease (e.g., lamotrigine).

Special precautions for use.

Treatment monitoring

Before prescribing the medicinal product, a thorough medical history should be taken and women should be advised to undergo a comprehensive gynecological examination to exclude pregnancy. The presence of menstrual cycle disorders such as oligomenorrhea and amenorrhea should also be assessed. The interval between examinations depends on individual circumstances. If the prescribed medication may affect a suspected or confirmed disorder, appropriate monitoring examinations should be scheduled accordingly.

Despite regular intake of Desofemono® 75, dysfunctional bleeding may occur. If bleeding occurs very frequently and irregularly, consideration should be given to switching to another contraceptive method. If symptoms persist, functional disorders should be ruled out.

The management of amenorrhea during contraceptive use depends on adherence to the instructions for tablet intake and may include a pregnancy test.

If pregnancy occurs, the drug should be discontinued.

Women should be informed that Desofemono® 75 does not protect against HIV infection (AIDS) and other sexually transmitted infections.

Warnings

If any of the conditions or risk factors listed below develop, the benefits of using progestin and the possible risks for each individual woman should be evaluated and discussed with her before initiating Desofemono® 75. In the event of exacerbation, recurrence, or initial onset of these conditions, the woman should consult a physician. The physician must decide whether continued use of Desofemono® 75 is appropriate.

Overall, the risk of breast cancer increases with age. During the use of COCs, the risk of developing breast cancer is slightly increased. This elevated risk gradually decreases over 10 years after discontinuation of COCs and depends not on the duration of COC use, but on the woman’s age at the time of COC use. The expected number of diagnosed breast cancer cases per 10,000 women who used COCs over 10 years after stopping COCs, compared to those who never used COCs, calculated for corresponding age groups, is presented in the table below.

The risk in women using progestogen-only contraceptives such as Desofemone® 75 may be comparable to that in women using combined oral contraceptives (COCs). However, evidence regarding progestogen-only contraceptives is less conclusive. Compared to the lifetime risk of developing breast cancer, the increased risk associated with COC use is low. Cases of breast cancer in women who have used COCs are generally less severe than in women who have not used COCs. The increased risk in women using COCs may be due to earlier diagnosis, the biological effect of the drug, or a combination of these two factors.

Since a biological effect of progestogens on liver cancer cannot be ruled out, the benefit-risk ratio should be individually assessed in women with liver cancer.

In case of acute or chronic impairment of liver function, women should consult a healthcare provider for examination and advice.

Epidemiological data indicate that the use of COCs is associated with an increased incidence of venous thromboembolism (VTE, deep vein thrombosis, and pulmonary embolism). Although the clinical significance of these data with respect to desogestrel used as a contraceptive in the absence of an estrogen component is unknown, Desofemone® 75 should be discontinued if thrombosis occurs. Desofemone® 75 should also be discontinued in cases of prolonged immobilization due to surgery or illness. Women with a history of thromboembolic disorders should be warned about the possibility of recurrence.

Although progestogens may affect insulin resistance and glucose tolerance, there is currently no evidence that treatment regimens need to be altered for women with diabetes mellitus who use progestogen-only contraceptives. However, diabetic women should be closely monitored during the first months of use.

If persistent arterial hypertension develops during use of Desofemone® 75, or if there is inadequate response to antihypertensive therapy in the case of significant blood pressure elevation, discontinuation of the medicinal product should be considered.

Use of Desofemone® 75 leads to a reduction in serum estradiol levels to those typical of the early follicular phase. It is currently unknown whether this reduction has any clinically significant effect on bone mineral density.

Progestogen-only contraceptives are less effective in preventing ectopic pregnancy than combined oral contraceptives, due to the frequent occurrence of ovulation during use of progestogen-only pills. Although Desofemone® 75 effectively inhibits ovulation, the possibility of pregnancy should be considered in differential diagnosis if a woman presents with amenorrhea or abdominal pain.

Chloasma may rarely occur, particularly in women with a history of chloasma gravidarum. Women prone to chloasma should avoid exposure to sunlight and ultraviolet radiation during use of Desofemone® 75.

Depressed mood and depression are well-known adverse reactions during use of hormonal contraceptives (see section "Adverse Reactions"). Depression can be severe and is a known risk factor for suicidal behavior and suicide. Women should consult a physician if mood changes or depressive symptoms occur, including shortly after starting treatment.

The following conditions have been reported during pregnancy and during use of sex steroid hormones, although a causal relationship with progestogen use has not been established: jaundice and/or pruritus associated with cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; hemolytic-uremic syndrome; Sydenham's chorea; herpes gestationis; hearing loss associated with otosclerosis; (hereditary) angioedema.

The effectiveness of Desofemone® 75 may be reduced in case of missed tablets (see section "Dosage and Administration"), gastrointestinal disturbances (see section "Dosage and Administration"), or concomitant use of medicinal products that reduce plasma concentrations of etonogestrel, the active metabolite of desogestrel (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Desofemone® 75 contains 46.15 mg of lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol (23 mg) of sodium per tablet, i.e., essentially "sodium-free".

Laboratory Tests

Data obtained from COCs indicate that hormonal contraceptives may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal, and kidney function, concentrations of (transport) proteins in serum (e.g., corticosteroid-binding globulin), lipid/lipoprotein fractions, carbohydrate metabolism parameters, and coagulation and fibrinolysis parameters. These changes usually remain within normal limits. It is unknown to what extent this also applies to progestogen-only contraceptives.

Use during Pregnancy or Breastfeeding

Pregnancy

Desofemone® 75 is contraindicated during pregnancy. If pregnancy occurs during use of Desofemone® 75, treatment should be discontinued immediately.

Animal studies have shown that very high doses of compounds with progestogenic activity may cause masculinization of female offspring.

Large epidemiological studies have not shown an increased risk of congenital malformations in children born to women who used COCs prior to pregnancy, nor teratogenic effects in cases of inadvertent COC use in early pregnancy. Pharmacovigilance data on various COCs containing desogestrel also do not indicate any increased risk.

Breastfeeding Period

Clinical study data have shown that Desofemone® 75 does not affect the production or quality (protein, lactose, or fat concentration) of breast milk. However, there have been isolated post-marketing reports of decreased breast milk production during use of Desofemone® 75. A small amount of etonogestrel is excreted into breast milk. As a result, the infant may receive 0.01–0.05 µg of etonogestrel per kilogram of body weight per day (based on an estimated milk intake of 150 ml/kg/day). Like other progestogen-only preparations, Desofemone® 75 may be used during breastfeeding.

Limited data are available from long-term follow-up of children whose mothers started desogestrel treatment between 4 and 8 weeks postpartum. These infants were breastfed up to 7 months and followed up to 1.5 years (n = 32) or 2.5 years (n = 14). Assessments of growth, physical, and psychomotor development showed no differences compared to infants whose mothers used a copper intrauterine device (IUD). Based on available data, Desofemone® 75 may be used during breastfeeding. However, careful monitoring of the infant's development and growth is recommended when the mother is using Desofemone® 75.

Fertility

Desofemone® 75 is indicated for the prevention of pregnancy. For information on the return of fertility (ovulation), see section "Pharmacodynamics".

Ability to Influence Reaction Speed When Driving or Operating Machinery

Desofemone® 75 has no effect or has a negligible effect on the ability to drive or operate machinery.

Method of administration and dosage

To achieve effective contraception, Desofemino® 75 should be used according to the instructions (see sections "How to take Desofemino® 75" and "How to start taking Desofemino® 75" below).

Method of administration

For oral use.

How to take Desofemino® 75

Tablets should be taken daily at approximately the same time each day, so that the interval between taking two tablets is always 24 hours. The first tablet should be taken on the first day of the natural menstrual cycle (i.e. the first day of menstrual bleeding). Then one tablet should be taken daily without interruption, regardless of possible bleeding. A new blister pack should be started the day immediately following the last tablet of the previous pack.

How to start taking Desofemino® 75

In the absence of prior use of hormonal contraceptives (within the past month)

Tablet intake should begin on day 1 of the woman’s natural menstrual cycle (i.e. the first day of menstrual bleeding). Starting on days 2–5 is acceptable, but in this case a barrier method of contraception is recommended during the first 7 days of tablet intake in the first cycle.

After first-trimester abortion

It is recommended to start taking the medicinal product immediately after first-trimester abortion. In this case, no additional contraceptive method is required.

After childbirth or second-trimester abortion

Women should be advised to start taking the medicinal product between day 21 and day 28 after childbirth or second-trimester abortion. If the initiation of treatment is delayed beyond this period, a barrier method of contraception should be used additionally during the first 7 days of tablet intake. However, if sexual intercourse has already occurred, pregnancy should be ruled out before starting Desofemino® 75, or the woman should wait for the first menstrual period. For use during breastfeeding, see also section "Use during pregnancy or breastfeeding".

How to start taking Desofemino® 75 when switching from other contraceptive methods

Switching from combined hormonal contraceptives (combined oral contraceptives [COCs], vaginal rings, or transdermal patches)

Women should preferably start taking Desofemino® 75 the day after taking the last active tablet (i.e. the last tablet containing active ingredients) of their previous COC, or on the day of removal of the vaginal ring or transdermal patch. In these cases, no additional contraceptive method is required.

Alternatively, women may start taking the product no later than the day after the end of the tablet-free interval or the end of patch or ring use, or after the placebo tablet period of their previous combined hormonal contraceptive. However, in this case, a barrier method of contraception is recommended during the first 7 days of tablet intake.

Switching from progestogen-only contraceptives ("mini-pills", injections, or intrauterine system releasing progestogen [IUS])

Women may switch to Desofemino® 75 at any day after discontinuation of the "mini-pill" (in case of an implant, on the day of removal; in case of an injection, instead of the next scheduled injection). No additional contraception is required.

Action to be taken in case of missed tablet intake

Contraceptive protection may be reduced if the interval between taking two tablets exceeds 36 hours. If less than 12 hours have passed since the missed tablet, the missed tablet should be taken as soon as remembered, and the next tablet should be taken at the usual time. If more than 12 hours have passed since the missed tablet, an additional contraceptive method should be used for the following 7 days. If a tablet was missed during the first week after starting Desofemino® 75 and sexual intercourse occurred during the week preceding the missed dose, the possibility of pregnancy should be considered.

Recommendations in case of gastrointestinal disorders

In case of severe gastrointestinal disorders, absorption may be incomplete; therefore, additional contraceptive measures should be taken.

If vomiting occurs within 3–4 hours after taking a tablet, absorption may be incomplete. In such a case, the recommendations provided in the section "Action to be taken in case of missed tablet intake" should be followed.

Special patient groups

Renal impairment

Clinical studies in patients with renal impairment have not been conducted.

Hepatic impairment

Clinical studies in patients with hepatic impairment have not been conducted. Since metabolism of steroid hormones may be impaired in patients with severe liver disease, desogestrel is not recommended for use in such women until liver function parameters return to normal (see section "Contraindications").

Children

The safety and efficacy of desogestrel in adolescents (under 18 years of age) have not yet been established. Data are lacking.

Overdose

No serious adverse effects have been reported following overdose. Symptoms of overdose may include nausea, vomiting, and slight vaginal bleeding in young girls. There is no specific antidote; treatment should be symptomatic.

Adverse reactions.

The most commonly reported adverse reaction during clinical trials was menstrual disorder. Menstrual disorders were observed in approximately 50% of women taking desogestrel. Since desogestrel (unlike other progestogen-only contraceptives) suppresses ovulation by nearly 100%, menstrual disturbances occur more frequently compared to progestogen-only preparations. In 20–30% of women, bleeding may become more frequent, whereas in another 20%, bleeding may become less frequent or cease altogether. Vaginal bleeding may also be prolonged. After several months of treatment, bleeding episodes tend to decrease in frequency. Information, counseling, and a diary recording all bleeding episodes can help women appropriately understand and manage bleeding patterns.

During clinical trials with desogestrel, the most frequently reported adverse reactions (> 2.5%) were acne, mood changes, breast pain, nausea, and weight increase. The adverse reactions are listed in the table below.

Adverse reactions are classified by frequency and by system organ class according to MedDRA [Medical Dictionary for Regulatory Activities] terminology.

* MedDRA (Medical Dictionary for Regulatory Activities), version 9.0.

Use of the medicinal product Desogestrel® 75 may result in the following adverse reactions: galactorrhea and rarely ectopic pregnancy (see section "Special Warnings and Precautions for Use"). In addition, angioedema (or its exacerbation) and/or worsening of hereditary angioedema may occur (see section "Special Warnings and Precautions for Use").

A number of serious adverse reactions have been reported in women taking (combined) oral contraceptives. These include venous and arterial thromboembolic events, hormone-dependent neoplasms (e.g., breast cancer), and chloasma; some of these are discussed in detail in the section "Special Warnings and Precautions for Use".

Breakthrough bleeding and/or loss of contraceptive efficacy may occur due to interactions of other medicinal products (microsomal enzyme inducers) with hormonal contraceptives (see section "Interactions with Other Medicinal Products and Other Forms of Interactions").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at temperatures not exceeding 30 °C, in a place inaccessible to children.

Packaging. 1, 3, or 6 blisters of 28 tablets each in a cardboard box.

Prescription status. Prescription only.

Manufacturer. mibe GmbH Arzneimittel.

Manufacturer's address and place of business.

Muenchener Strasse 15, Brehna, Saxony-Anhalt, 06796, Germany.